2-trifluoromethylbenzimidazoles

ABSTRACT

2-TRIFLUOROMETHYLBENZIMIDAZOLES HAVING A SULPHAMONYL OR SUBSTITUTED SULPHAMOYL SUBSTITUENT ON THE BENZENE ING COMBAT MAMMALIAN PARASITES, FOR EXAMPLE LIVER FLUKE IN MAMMALS E.G. SHEEP, AND CATTLE TICK AND SHEEN BLOWFLY.

United States Patent Oflice Patented July 9, 1974 3,823,154 Z-TRIFLUOROMETHYLBENZIMIDAZOLES John Roger Corbett, Linton, and Albert Percival Hauxton, England, assignors to Fisons Limited, London, England No Drawing. Filed July 23, 1971, Ser. No. 165,696 Claims priority, application Great Britain, July 29, 1970, 36,673/70; Mar. 16, 1971, 7,044/ 71 Int. Cl. C07d 49/38 US. Cl. 260-309.2 14 Claims ABSTRACT OF THE DISCLOSURE "2-Trifluoromethylbenzimidazoles having a sulphamoyl or substituted sulphamoyl substituent on the benzene ring combat mammalian parasites, for example liver fluke in mammals e.g. sheep, and cattle tick and sheep blowfly.

SOzNRR or a therapeutically acceptable salt thereof, in which R and R which may be the same or different, each represent hydrogen, aryl, substituted aryl (for example aryl substituted by halogen and/or alkyl), alkyl, substituted alkyl (for example alkyl substituted by hydroxy, alkoxy, halogen and/or dialkylamino), cycloalkyl of from 3 to 8 carbon atoms (for example cyclopropyl or cyclohexyl), alkenyl (for example allyl) or alkynyl (for example propargyl), or R and R together with the nitrogen atom to which they are attached, form a heterocyc-lic radical (for example piperidino or morpholino);

R R and R which may be the same or different, each represent hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl (for example alkyl substituted by halogen, e.g. trifluoromethyl), alkoxy, aryloxy, alkylthio or an oxygenated derivative thereof (for example-SO alkyl or -SO alkyl) arylthio or an oxygenated derivative thereof (for example -*SO aryl or SO aryl) or a further SO NR R group (in which R and R are as delfined above); and

R represents hydrogen, alkyl or the group O(:X)YLR in which M and Y, which may be the same or difierent, each represent oxygen or sulphur and R represents alkyl, aryl, substituted alkyl (for example alkyl substituted by hydroxy, alkoxy and/or halogen), substituted aryl (for example aryl substituted by halogen and/or alkyl), alkenyl (for example allyl), alkynyl (for example propargyl) or cycloalkyl of from 3 to 8 carbon atoms (for example cyclohexyl).

Alkyl in this specification means alkyl of up to 12, usually up to 6, carbon atoms, e.g. methyl, ethyl, normalor iso propyl or normal-butyl; alkoxy, alkenyl, alkynyl and alkylthio are analogous. Aryl may be for example phenyl or naphthyl; aryloxy and arylthio are analogous.

The invention provides also a parasiticid'al composition comprising such a compound together with a therapeutically acceptable carrier, particularly a sterile carrier.

The invention also provides an anthelmint-ic composition comprising -1500 mg. of such a compound together with a pharmaceutically acceptable carrier, the composition being in unit dosage form. Thus, it may be in the form of a tablet or a capsule containing the composition. The composition may be solid.

In addition, the invention provides a preferred compound which is a substituted benzimidazole of formula or a therapeutically acceptable salt thereof, in which R and R which may be the same or different, each represent hydrogen or alkyl of up to 12 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a heterocyclic ring; and

R R and R, which may be the same or dilferent, each represent a halogen atom. The invention also provides a process for preparing such a compound, which process comprises reacting the corresponding benzimid'azole sulphonyl chloride of formula with an amine of formula HNRR The present compounds of formula I may be used to combat external animals parasites, e.g. cattle tick or sheep blowfly. The compounds are however, particularly valuable as anthelmintics.

Usually in the present compounds R and R which may be the same or dilferent, each represent hydrogen; phenyl; phenyl substituted by halogen or by alkyl of up to 6 carbon atoms; alkyl of up to 6 carbon atoms; alkyl of up to 6 carbon atoms substituted by hydroxy, alkoxy of up to 6 carbon atoms, halogen or by dialkylarnino whose alkyl groups each contain up to 6 carbon atoms; cycloalkyl of 3-8 carbon atoms; allyl; or propargyl or R and R together with the nitrogen atom to which they are attached, form a piperidino or morpholino radical;

R R and R which may be the same or different, each represent hydrogen; halogen; nitro; cyano; alkyl of up to 6 carbon atoms; alkyl of up to 6 carbon atoms substituted by halogen; alkoxy of up to 6 carbon atoms; phenyloxy; alkylthio of up to 6 carbon atoms; phenylthio or a further SO NRR group; and

R represents hydrogen, alkyl of up to 6 carbon atoms or the group in which Y represents oxygen or sulphur and R represents alkyl of up to 6 carbon atoms; phenyl; alkyl of up to 6 carbon atoms substituted by hydroxy, alkoxy of up to 6 carbon atoms or by halogen; phenyl substituted by halogen or by alkyl of up to 6 carbon atoms; allyl or propargyl.

In a preferred group of the compounds R and R which may be the same or different, each represent hydrogen, alkyl of up to 6 carbon atoms, dialkylaminoalkyl whose alkyl groups each contain up to 6 carbon atoms, chlorine-substituted phenyl, hydroxyalkyl of up .to 6 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a piperidino radical;

R R and R which may be the same or different, each represent hydrogen or halogen, at least two of them being halogen; and

R represents hydrogen or COOR where R represents alkyl of up to 6 carbon atoms.

Any halogen (i.e. chlorine, bromine, iodine or fiuorine) is generally chlorine for convenience in preparation. In one embodiment one or none of R R and R represent hydrogen. The SO NRR group in formula I is often on the 4- or 7-position.

By reason of a combination of low mammalian toxicity and high parasiticidal, especially anthelmintic activity, compared with compounds closely related chemically, it is preferred that the compound be a substituted benzimidazole of formula:

NS Oz Llt R (II) or a therapeutically acceptable salt thereof, in which R and R which may be the same or different, each represent hydrogen or alkyl of up to 12 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a heterocyclic ring; and

R R and R, which may be the same or different, each represent a halogen atom.

Usually in this preferred group of formula H, R and R which may be the same or different, each represent hydrogen or alkyl of up to 12 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a piperidino or morpholino radical.

Preferred within this preferred group are compounds wherein R and R which may be the same or different, each represent hydrogen or alkyl of up to 6 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a piperidino radical; and

R, R and R which may be the same or different, each represent a chlorine or bromine atom.

In the present compounds of formula I, it is preferred that one or preferably both of R and R be othen than hydrogen.

tAn especially preferred goup of compounds by reason of an exceptionally good combination of low mammalian toxicity and high parasiticidal, especially anthelmintic, activity, is of formula II above where R and R each represent an ethyl group and R R and R which may be the same or different, each represent a chlorine or bromine atom.

Particular benzimidazoles are specified in the Examples. Particularly preferred specific compounds are:

5,6,7-trichloro-N,N-diethyl-2-trifluoromethylbenzimidazole-4-sulphonamide; 7-bromo-5,6-dichloro-N,N-diethyl-2-trifiuoromethylbenzimidazole-4-sulphonamide; 5,6,7-tribromo-N,N-diethyl-Z-trifluoromethylbenzimidazole-4-sul-phonamide; and 5,7-dibromo-6-chloro-N,N-diethyl-Z-trifiuoromethylbenzimidazole-4-sulphonamide;

and their therapeutically acceptable salts.

The present compounds may be prepared by a process which comprises reacting the corresponding benzimidazole sulphonyl chloride of formula S 0: C1 R with an amine of formula I-INRR where R, R R R R and R are as defined under formula I.

Compounds where R is C(:X)YR e.g. COOR may also be prepared by a process which comprises reacting the corresponding benzimidazole sulphonamide of formula I where R represents a hydrogen atom with a chloroformate of formula ClC(:X)YR e.g. CICOOR It will be appreciated that some of the present compounds may exist in tautomeric forms. R may be on either of the imidazole nitrogen atoms. For convenience, only one form is named, but the present invention embraces both forms.

It will also be appreciated that for reasons of solubility etc., the present substituted benzimidazoles which form such salts may well be used in the form of therapeutically acceptable salts, and whether any particular salt is therapeutically acceptable can of course readily be determined. A salt which is acceptable for external treatment may of course not be acceptable for internal treatment. A salt is therapeutically acceptable for purposes of scope of the present compounds if it is therapeutically acceptable for any of the present treatments.

Suitable salts of the substituted benzimidazoles embraced by the present invention in which R represents hydrogen include ammonium salts, metal salts such as for example sodium, potassium, calcium, zinc, copper and magnesium salts, amine salts such as for example methylamine, ethylamine, dimethylamine, triethylamine, ethanolamine, triethanolamine and benzylamine salts. According to a preferred embodiment the salts are alkali metal salts. Generally the akali metal salts are crystalline solids, readily soluble in water. Especially preferred, however, are N-methyl-glucamine salts.

The salts may be prepared by reacting the benzimidazole in aqueous or aqueous-organic solvent solution or suspension with an alkaline compound of the metal, such as the hydroxide, or with the amine or ammonia, as appropriate. The metal salts may also be prepared by metathesis for example between the alkali metal salt of the benzimidazole and a salt of the metal. Some of the benzimidazoles are also basic and can form salts with strong acids such as hydrochloric acid.

Salts with acids, e.g. strong acids such as hydrochloric acid, may also be formed by reason of the SO NRR part of the molecule.

The present compounds possess parasiticidal activity. They are particularly valuable as anthelmintics (e.g. as fasciolicides) but they also possess activity against external parasites, e.g. blowfly and tick. For any of these uses the compounds may be used to inhibit infection or to treat an infection already present.

The compounds are generally used in the form of compositions, and these usually contain a therapeutically acceptable carrier and/or surface active agent. The compositions may be prepared by a process comprising admixing the ingredients. For some treatments the composition should of course be sterile.

The carrier may be water. Many of the salts of the substituted benzimidazoles embraced by the invention are water-soluble, and these may be used as aqueous solutions with or without surface active agents or organic solvents.

If desired, the substituted benzimidazole or salt thereof may be dissolved in a water immiscible solvent, such as for example a hydrocarbon of boiling point 130 to 250 C., which may contain a dissolved surface active agent.

The substituted benzimidazole or salt thereof may be admixed with a surface active agent with or without a car- The term surface active agent is used in the broad sense to cover materials variously called wetting agents, emulsifying agents and dispersing agents. Such agents are well known in the parasiticide art.

rier. The compositions may contain other parasiticidal com- The carrier may be a solid, e.g. talc, chalk, gypsum or pounds or other compounds which stimulate the growth earths, with or without surface active agents. or health of the animal.

The main use envisaged is as anthelmintics. For anthel- The present compounds are useful because they possess mintic use, the compounds may be administered orally or pharmacological activity in animals. In particular, the parenterally, and may be administered as a pharmaceuti- 10 compounds are anthelmintics as indicated by anthelminthic cal preparation with a pharmaceutically acceptable cartests in rats and sheep. For this use, the dosage rate will, rier, e.g. in a tablet or capsule, or may be admixed with of course, depend on such factors as the particular comthe drinking water or food for the animals. Animals in pound employed, its toxicity, the treatment desired and which use is envisaged include domestic and farm animals, the animal treated. In general, however, the dosage is e.g. sheep, pigs, cows, horses, dogs and cats, and animals about 2-250 mg. of active ingredient per kilogram of body for use in laboratories, e.g. mice, rats, hamsters and guinea weight. A single dose may be sufficient, or it may be repigs. The compounds may also be administered to human peated if necessary. For the larger mammals, a suitable beings. They are particularly active against liver fluke dose is about 150-1500 mg. The compounds are also (Fasciola hepatica). parasiticides for external animal parasites as indicated by Formulations for adding to drinking water may intests on sheep and cows. For such use, the amount of clude surface active agents to ensure satisfactory solution active ingredient may be between 0.01 and 0.5% by weight or dispersion. of the total composition, e.g. spray, dip or drench, use.

Formulations for adding to foods may consist of the The invention is illustrated by the following Examples, compound alone or be mixed with physiologically 210- in which parts and percentages are by weight and temceptable carriers such as talc, chalk, gypsum or earths, peratures are in degrees Centigrade unless otherwise inwith or without surface active agents. dicated.

The compounds may be formulated by impregnating EXAMPLE 1 or coating a granule, for example a gypsum granule, with them- 5,6,7-Trichloro-N,N-diethyl-2-trifiuoromethyl- A composition may contain as carrier a foodstuff for the benzimidazole 4 sulphonamide animal.

The Surface active agents may comprise anionic 5,6,7-Trichloro 2 (trifiuoromethyl)-4-benzimidazolepounds for example soaps, fatty sulphate esters such as sulphonyl chloride 2 pal-ts) in dry acetone (80 parts) dodecyl sodium sulphate, fatty aromatic sulphonates such was added dropwise to a solution f diethylamine (12 as alkyl-benzene sulphonates or butyl naphthalene sulparts) in dry acetone (16 parts). The temperature was Phonates, more complex fatty sulPhona'ltes Such as the kept below 30 and the reaction mixture stirred for two amide condensatlon Product of 1e1c ac1d and N'methyl hours. The solvent was evaporated and the residue treated taurifle the sodium sulphonate of dloctyl fi with 6 N hydrochloric acid. The solid product was col- The surfiwe actlve agents may also compnse non-1091c lected, washed with water and dried (23 parts). Recrystalsurfact active agents such as for example condensation 40 Elation from toluene (charcoal) gave the required prod products of fatty acids, fatty alcohols or fatty substituted net as pale coloured needles (2L6 parts; [melting phenols with ethylene oxide, or fatty esters and ethers of Point] 1524543; 89 7% sugars or polyhydric alcohols, or the products obtained Found: C 333; H, 245; N cmHnclsFaNsozs from the latter by condensation with ethylene oxide, or quires: C 3395. H 99%. the products known as block copolymers of ethylene oxide and propylene oxide. The surface active agents may also EXAM L S 240 comprise cationic agents such as for example cetyl trimethylammonium bromide. The following were prepared by a similar method:

R1 R I N -CF5 R \N H R Analysis (percent) M m Found Requires 533E82 R, R, R3 R4 degrfes gis e fi zde gr s) o H N o H N 2 sozNwnm C1 C1 Cl 243-244 Xylene 30.55 2.0 10.45 30.3 1.8 10.6 SO2N(X1C3H7)2 01 Cl 01 -146 Petrol (s0-100) 36.85 3.5 9.35 37.15 3.35 9.3 302100506311 C1 C1 Cl 179-130 Petrol (l00-l20)- 30.75 3.15 9.3 37.15 3.35 0.3 so2N(n0.H,)2 C1 C1 CI 93-95 Petrol (40-60)--." 39.8 3.9 8.9 39.95 4.0 8.75 S02NHC H -n 01 Cl 01 152-153 Petrol (100-120)-.- 34.1 2.3 9.65 33.95 2.6 9.9

02H. 01 C1 Cl 241-243 Nitromethane.--.- 33.3 3.2 11.0 33.35 3.4 11.1 SO NH(CH2)zl| T-HCL 8 c1 c1 c1 01 234-230 do 32 35 1.5 7.85 32.75 1.0 3.15

So.NH a

9 SOgN(CEHzCHgOH)2 Cl Cl 01 -166 .....d0 3135 2.5 9.05 31.55 2.45 9.2

TABLE-Continued Analysis (percent) Found Requires Example M.P., Recrystallislng number R R; R; R4 degrees solvent (degrees) H N G H N 01 I C1 Cl 236-238 Ethanol 35.45 2.6 9.55 35.75 2.55 9.6

11- SOzN(CHs)z C1 C1 H 169-171 Nitromethane 32.8 2.5 11.35 33.15 2. 25 11.6

12 SO N(CZH )2 C1 01 H 120-131 Petrol (80-100) 36.65 2.85 10.65 36.95 3.1 10.75

13 SOzN(nC H )z C1 01 H 103-104 do 40. 35 3.45 10.2 40.2 3.85 10.05

14 SOzN(isoC3H )g C1 C1 H 146-147 Nitr0methane 40. 25 3.75 10. 15 40.2 3.85 10.05

15 SO N(nC4H C1 C1 H 60-62 Petrol (below 40).. 42.65 4.3 9.3 43.05 4.5 9.4

16 sozNHnCiH Cl 01 H 145-146 Petrol (100-120) 36.70 3.05 10.45 36.95 3.1 10. 75

17 SO NHC H C1 01 H 89-91 Toluene 33.2 2.25 11.35 33.15 2. 25 11.6

18 01 H 80; H 142-143 Benzene 40.25 3.4 11.6 40.5 3.7 11.8

N(C2 s)2 19 N0 H Same H 120-121 Petrol (100-120)-- 39.05 3.3 15.3 39.35 3.6 15.3

20 H H do H 89-91 Dilute ethanol 44.85 4.4 13.05 44.5 4.6 12.75

EXAMPLES 21-26 The following compounds of formula II were prepared by a similar method:

Melting Example No. R R P. R R point Q2115 C1 Cl Br 188-190 CzHs Br Br Br 175-177 CzHs Br C1 B1 177-178 C2H5 Br 01 Cl 153-155 CzHs Cl Br Cl 169-171 OH: Cl Br 01 203-205 EXAMPLE 27 Isopropyl 5, 6-dichloro-4- (diethylsulphamoyl) -2- (trifiuoromethyD-1-benzimidazolecarboxylate Isopropyl chloroformate (2 parts) in acetone (8 parts) was added to a solution of 5,6-dichloro-N,N-diethyl-2-(trifluoromethyl)-4benzimidazolesulphonamide (6 parts) in acetone (16 parts) containing triethylamine (1.6 parts), stirred at room temperature for one hour, filtered off the hydrochloride and the filtrate was evaporated to dryness. The residue was recrystallised from ethanol to give white needles of the required product (3.2 parts; mp. 133- 135).

FOUI'ld: C, H, 3.7; N, 9.1. C16H18C12F3N3O4S requires: C, 40.35; H, 3.8; N, 8.8%.

EXAMPLE 28 Similarly ethyl 5,6-dich1oro 4 (diethylsulphamoyl)-2- (trifluoromethyl) 1 benzimidazolecarboxylate was prepared (m.p. 168-169', from ethanol).

Found: C, 38.65; H, 3.8; N, 8.8. C H Cl F N O S requires: C, 38.95; H, 3.5; N, 9.1%.

EXAMPLE 29 1 ml. aliquots of an acetone solution of the product of Example 1, containing 1000, 300, 100, 30 and 10 p.p.m. (parts per million), were applied to cotton wool dental rolls 1 cm. diameter x 2 cms. After drying these were placed in glass vials 2 ems. diameter x 5 cms. and closed by a cotton wool plug.

The treated cotton wool rolls were then impregnated with 1 ml. sheep serum and infested with first instar larvae of the sheep blowfly, Lucilia sericata, then held at C. for 24 hours.

The percentage mortality of the parasites was then recorded, when it was found that the treatments had killed more than 95% as compared with less than 5% in controls.

EXAMPLES TO same result was obtained.

EXAMPLES 36 TO 38 The experiment described in Example 29 was also applied to the products of Examples 4, 5 and 14, but with the following dosage rates: 1000, 300, 100 and 30 p.p.m. The same result was obtained.

EXAMPLE 39 1 ml. aliquots of an acetone solution of the product of Example 1, containing 1000, 300 and 100 p.p.m., were applied to filter papers, 9 cm. in diameter. These were allowed to dry then folded into quadrant shaped packets.

The treated papers were then infested with first stage larvae of the cattle tick, Boophilus microplus, closed by a metal clip and held at 25 C. for 24 hours.

The percentage mortality of the ticks was then recorded, when it was found that each of the treatments had killed more than of the ticks as compared with less than 5% in controls.

EXAMPLES 40 TO 47 The experiment described in Example 31 Was also applied to the products of Examples 2, 3, 4, 5, 6, 11, 12 and 13. The same result was obtained.

EXAMPLE 48 The experiment described in Example 39 was also applied to the product of Example 14, except that the dosage rates were 1000, 300, and 30 p.p.m. The result was the same.

EXAMPLES 49 TO 57 Three week old rats (Wistar strain) were infected orally with 30 metacercaria of the liver fluke, Fasciolo hepatica. Forty days after infection, when most of the flukes had become established in the bile duct, the rats were administered orally with 2% suspensions in tragacanth of the benzimidazole derivatives listed below at the rates indicated. Five rats were used at each dosage rate of each compound. The dosage rates used were governed by the acute oral LD to rats as determined by preliminary toxicological studies.

Six days after administration, the rats were killed and the bile duct dissected to determine the number of mature flukes surviving. Results'are tabulated below as the percentage fluke reduction in comparison with unmedicated control animals.

Rate of treatment (mg.flrg.)

Example number Compound 187 93 46 23 Product of Example 1--. 91 45 50-. Product of Example 21.- 85 51-. Product of Example 22 90 65 52 Product of Example 23 90 78 53 Product of Example 2 60 54 Product of Example 3... 55.. Product of Example 6. 56..-- Product of Example 24 57 Product of Example 25..

EXAMPLE 58 Example 49 was carried out but with a 0.66% tragacanth suspension of the compound. The same result was obtained.

EXAMPLES 59 TO 66 Three week old rats (Wistar strain) were infected orally with 30 metacercaria of the liver fluke, Fasciola hepatica. Fourteen days after infection, when a high percentage of the migrating flukes were still in the liver parenchyma, the rats were administered orally with 2% suspensions in tragacanth of the benzimidazole derivatives listed below at the rates indicated. Five rats were used at each dosage rate of each compound. The dosage rates used were governed by the acute oral LD to rats as determined by preliminary toxicological studies.

Six days after administration, the rats were killed and their livers minced to liberate the surviving immature ilukes. These were compared with unmedicated control animals and the results tabulated below as the percentage fluke reduction.

Rate of treatment (mg/kg.)

Three week old rats (Wistar strain) were infected orally with 30 metacercaria of the liver fluke, Fasciola hepatica. Forty days after infection, when most of the fiukes had become established in the bile duct, the product of Example 3was administered orally as a 1.35% tragacanth/ arachis oil solution/ suspension at a rate equivalent to 94 mgs. active ingredient per kgof body weight. The dosage rate used was governed by the acute oral LD as determined by preliminary toxicological studies. Five rats were used.

Six days after the compound was administered, the rats were killed and the bile duct dissected to determine the number of mature flukes surviving. It was found that the reduction of flukes in each treatment was 80% in comparison with unmedicated controls.

EXAMPLE 68 Three week old rats (Wilstar strain) were infected orally with 30 metacercaria of the liver fluke, Fasciola hepatica. Forty days after infection, when most of the fiukes had become established in the bile duct, the product of Example 6 was administered orally as a 3.7% tragacanth/ arachis oil solution/ suspension at rates equivalent to 188 and 94 mgs. active ingredient per kg. of body weight. The dosage rates used were governed by the acute oral LD as determined by preliminary toxicological studies. Five rats were used at each dosage rate.

Six days after the compound was administered, the rats were killed and the bile duct dissected to determine the number of mature fiukes surviving. It was found that the reduction of fiukes in the respective treatments was 90 and 40% in comparison with unmedicated controls.

EXAMPLE 69 Sheep known to be free from liver fluke disease were each infected with 300 Fasciola hepatica metacercaria.

The product of Example 1 was administered by subcutaneous injection of an aqueous solution of its Nmethyl-glucamine salt. The effect of the product against immature and adult liver flukes was determined by administering the compound to two sheep four weeks after infection and to two other sheep twelve weeks after infection.

All the sheep, as well as untreated control animals, were slaughtered 13 weeks after infection and the flukes present in each animal were counted.

Efliciency of the treatment was assessed by comparing the number of flukes in treated animals with the number in the untreated controls.

The results are shown below:

Age of infection at time of No. of treatment flukes Percent Dose rate (mg/kg.) (weeks) recovered reductions 4 29-9 75 12 276 82 4 0-2 99 12 0-0 100 Untreated controls. 38-111 A dose of 12 mg./kg. was completely effective against fluke infections of four weeks and twelve weeks duration.

The lower dose of 6 mg./kg. gave a high degree of activity against both ages of fluke although complete cures were not achieved.

EXAMPLE 70 The experiment described in Example 68 was also applied to the product of Example 7.

It was found that the reduction of fiukes in the treatments at 188 and 94 mg./ kg. was respectively 75 and 65% in comparison with unmedicated controls.

The benzimidazole sulphonyl chlorides of formula III which may be used in the preparation of the present active compounds may be prepared by reacting the corresponding benzimidazole sulphonic acid with thionyl chloride, preferably in the presence of dimethylformamide as catalyst. The use of dimethylformamide has been found to result in a surprising increase in yield. The benzimidazole sulphonic acid may be prepared by sulphonation of the corresponding benzimidazole derivative of formula where R R R and R are as defined under formula I, suitably by means of oleum. These processes are illustrated by the following Examples.

EXAMPLE 71 (a) 4,5,6 trichloro 2 'trifiuoromethylbenzimidazole parts) was added gradually to stirred oleurn (1260 parts) and the mixture then refluxed for two hours. After cooling, the mixture was poured into water (3000 parts), the temperature being allowed to rise to near boiling. The mixture was cooled to room temperature overnight and the crystalline product was filtered off, washed with water and dried to give 165.9 parts (92% yield) of 5,6,7 trichloro 2 trifluoromethylbenzimidazole 4- sulphonic acid.

EXAMPLE 72 (b) The 5,6,7-trichloro-2-trifluoromethylbenzimidazole- 4-sulphonic acid parts) was added to a stirred mixture of thionyl chloride (770 parts) and dirnethylformamide (24 parts). A vigorous effervescence took place,

and when this had subsided the mixture was slowly heated each represent a chlorine or bromine atom.

to reflux temperature (80 C.) and maintained at this 4. A compound according to claim 1 wherein one or temperature for three hours. The reaction mixture was both of R and R is other than hydrogen.

then cooled and the solid crystals filtered ofl, washed with 5. A compound according to claim 4 wherein both R benzene (160 parts) and dried to give 5,6,7-trichloro-2- and R are other than hydrogen. trifluoromethylbenzimidazole-4-sulphonyl chloride (138 6. A compound according to claim 1 wherein parts), melting point (with decomposition) 208-209 C. R and R each represent ethyl; and

Evaporation of the filtrate yielded a further parts of R R and R, which may be the same or difi'erent,

the product, giving a total yield of 148 parts (91% yield). each represent a chlorine or bromine atom.

EXAMPLE 73 1O 7. A compound according to claim 1, which is a therapeutically acceptable salt of 5,6,7-trichloro-N,N-di- (c) Diethylamine 102 parts) was added dropwise to a ethyl-2-trifluoromethylbenzimidazole-4-sulphonamide. suspension of the 5,6,7-trichloro-2-trifiuoromethylbenzi- 8. A compound according to claim 1, which is a midazole-4-sulphonyl chloride (136 parts) in acetone (400 therapeutically acceptable salt of 7-bromo-5,6-dichloroparts) cooled in an ice bath to maintain a temperature N,N-diethyl-2 trifluoromethylbenzimidazole-4-sulphonof about C. After the addition of all the diethylamine, amide.

the mixture was stirred for 15 minutes and then poured 9. A compound according to claim 1, which is a into excess ice/water. The resulting solution was acidified therapeutically acceptable salt of 5,6,7-tribromo-N,N-diwith concentrated hydrochloric acid to precipitate a cream ethyl-Z-trifluoromethyl-benzimidazole-4-sulphonamide. solid which was filtered off, washed with 'Water and dried 2O 10. A compound according to claim 1, which is to give 5,6,7 trichloro-N,N-diethyl 2 trifiuoromethyltherapeutically acceptable salt of 5,7-dibromo-6-chlorohenzimidazole-4-sulphonamide (144 parts, 97% yield), N ,N-diethyl-Z-trifluoromethyl benzimidazole-4-sulphonmelting point 155-157 C. amide.

EXAMPLES 7 11. 5,6,7-trich1oro-N,N-diethyl-2-trifluoromethyl-benz 25 imidazole-4-sulphonamide. The following other compounds were prepared by proc- 12. 7-bromo-5,6 dichloro-N,Ndiethyl-2 trifiuoroesses analogous to those of Examples 71-73: methyl-benzimidazole-4-sulphonamide.

Yield at- Melting Compound point, 0. Stage (a) Stage (b) Stage (0) 7-b1rltlmilo-5gdihlor0-N,N-diethyl-2-tritluoromethylbenzimidasole-4- 183-5 94% (Ex. 74) 91.6% (Ex. 75)- 96% (Ex. 76).

S 011 m1 e. 5,7-dEbromo-6chloro-N,N'diethyl-2-trifluoromethylbenzimidazolei- 1735 94% (Ex. 77) 89.6% (Ex. 78). 89% (Ex. 79).

sulphonamide.

What is claimed is: 13. 5,6,7-tribromo-N,N-diethyl 2-trifiuoromethyl-benz- 1. A compound which is substituted benzimidazole of imidazole-4-sulphonamide. formula 14. 5,7-dibromo-6-chloro N,N-diethyl-Z-trifiuorometh- R ylbenzimidazole-4-sulphonamide.

R N\ References Cited UNITED STATES PATENTS R f 3,687,870 8/1972 Muzyczko et al. 260556 B B ]& 3,412,101 11/1968 Zwahlen 260309.2 \N80: 3,418,318 12/1968 Lambie 260309.2 R (11) FOREIGN PATENTS or a therapeutically acceptable salt thereof, in which R 1,053,204 12/1966 Great i i "1" 260556 B and R which may be the same or different each reprer0 1,122,988 8/1968 Great Bmam 260 309-2 sent hydrogen or alkyl of up to 6 carbon atoms, or 0 -R and R together with the nitrogen atom to which OTHER REFERENCES they are attached, from piperidino or morpholino ring; Conant 6t The Chemistry Of Organic Compounds 4th and ed., pp. 419-20, =N.Y., MacMillan, 1952. R, R and R, which may be the same or difierent, each Fieser 6t Organic Chemistry, P- B05101! Heath,

represent a halogen atom. 2. A compound according to claim 1, which is the Flesef Reagents for Organic Synthesis, PP- benzimidazole of formula II. 287, 1158 and 1159, Wiley, 1967.

3. A compound according to claim 1 wherein R and R which may be the same or difierent, each NATALIE TROUSOF Pnmary Exammer represent hydrogen or alkyl of up to 6 carbon atoms, or R and R together with the nitrogen atom to which they are attached, from piperidino; and 260247.1, 293.6; 424-248, 267

R R and R which may be the same or different, 

